Hydroindolo[2, 3-alpha]quinolizines



United States Patent O F 3,087,930 HYDROINDOLOH,S-OJQUINOLIZINES RobertN. Schut, Edwardshurg, MiclL, assignor to Miles Laboratories, Inc,Elkhart, Ind, a corporation at Indiana No Drawing. Filed Aug. 9, 1961,Ser. No. 131,961

7 Claims. (Cl. 260288) in which R and R may represent hydrogen or loweralkyl groups and R may represent an alkyl or aryl group.

In addition, the invention is concerned with the provision ofderivatives of these indolo quinolizines, particularly the ketals andvarious salts of these compounds.

The indolo quinolizine corresponding to the ttormula-- is also includedWithin this invention and, as pointed out below, may be similarlyprepared. The invention is also concerned with salts of these compounds.It may be seen from a comparison of the two formulae given above thatthe second compound is related to the first series of compounds in thatR and R of the first series together represent the tetramethylene groupin the second.

These compounds may be conveniently prepared by means of a syntheticscheme which involves a series of steps beginning with the condensationof tryptamine with the hydroxymethylene derivative of an a e-unsaturatedketone (II). The condensation may be conveniently conducted in aqueoussolution at room temperature. The condensation product (III) is thenreacted with methanolic hydrogen chloride and the resulting intermediate(IV) is converted to the desired compounds by means of heating withsodium bicarbonate or other base in an aqueous methanolic or otheralcoholic medium. The re- 3,087,930 Patented Apr. 30, 1963 actionsequence may be seen in the following series of equations- C H NH .1101E 1 NH Ra 2 /R2 (1) i i The free bases (V) produced in accordance withthe synthesis outlined above may be readily converted to various salts,or ketals of the compounds may be formed by treatment of the free basewith alcoholic hydrogen chloride. For example, where methanol is usedthe dimethyl ketal hydrochloride results. If isopropyl alcohol isusedinstead of the methyl alcohol, however, the ketal is not formed andthe hydrochloride results instead.

Each of the reactions described above may be carried out under mildconditions. The product can in most cases be obtained in an overallyield of about 50% to In order to prepare the corresponding dodecahydroderivatives, the use of an appropriate starting material in which theunsaturated ketone is a cyclohexene derivative is necessary.

The invention will be better understood by reference to the followingexamples which are included for purposes of illustration and are not tobe construed as in any way limiting the scope of the instant inventionwhich is defined in accordance with the claims appended hereto.

EXAMPLE I 1,2,3,4,6,7,12,12b Octahydr0-2-Ox0-4,4-Dimethylindolo-[2,3-a1Quinolizine, Hydrochloride and Dimezhyl Ketal Hydrochloride A.Sodio hydroxymethylene derivative of mesityl 0xide.-To a stirredsuspension of 27 g. (0.50 mole) of freshly prepared sodium methoxide in200 m1. of anhydrous ether was added a mixture of 49 g. (0.50 mole) ofmesityl oxide and 37 g. (0.50 mole) of ethyl formate in ml. of otherover a 1-hour period (N atmosphere, 0-5"). The mixture was stirred anadditional hour, then filtered. The crude product was washed with etherand dried in the vacuum dessicator at room temperature; yield 27 g.(36%).

B. N-tryptaminomethylene mesityl 0xide.A solution of 7.78 g. (0.039mole) of tryptamine hydrochloride in Found: Cl, 11.49.

OHCl M0011 max 1620 cm. k

The nitrogen analysis indicated 94.5% purity.

Analysis.Calcd. for C H N O: N, 10.44. Found: N, 9.88.

C. 1-(2-0x0-4-methyl-3-pentenyl)-1,2,3,4 tetrahydro- B-carbolinelzydroclzloride.-A solution of 8.5 g. (0.032 mole) ofN-tryptaminomethylene mesityl oxide in 50 ml. of methanol was saturatedwith hydrogen chloride. Ether (50 ml.) was added and the solution wasallowed to cool for 2 hours. The ivory-colored crystalline salt wasfiltered and washed with methanol-ether to give 3.1 g. of product, M.P.205-210 (dec.). Second and third crops isolated from the filtrateincreased the yield to 5.7 g. (59%). The infrared spectrum (KBr) showedbands at 1680 (C=O, conj.) and 1620 cm. (C=C, conj.).

Analysis.Calcd. for C H ClN O: Cl, 11.64. Found Cl, 11.73.

D. 1,2,3,4,6,7,12,12b octalzydro-Z-x0-4,4-dimethylind0l0[2,3]quin0lizineand hydr0clzl0ride.-A mixture of 4.98 g. (0.0163 mole) of thetetrahydro-fl-carboline hydrochloride described above, 100 ml. ofethanol and 50 ml. of sodium bicarbonate solution was heated underreflux for 2 hours. The mixture was cooled and the crystalline productfiltered and washed with a little cold aqueous alcohol. The yield was4.20 g. (96%), M.P. 225-227;

The analytical sample was produced by recrystallization from 95%methanol, M.P. 227-227".

Analysis.-Calcd. for C H N O: N (basic), 5.22. Found: N, 5.18(titration).

A 10-g. sample of the free base in 100 ml. of warm isopropyl alcohol wastreated with a solution of 4 g. of hydrogen chloride in 50 ml. ofisopropyl alcohol. The hydrochloride salt precipitated immediately.Recrystallization was accomplished by addition of just enough water todissolve the salt. The solution Was cooled and the 1710 cm." (normalketone C=O) precipitated crystalline hydrochloride was filtered, washed0 with cold isopropyl alcohol and dried to give 6.5 g. of product, M.P.230-235 (dec.).

Analysis.Calcd. for C H ClN O: Cl, 11.64.

E. 1,2,3,4,6,7,l2,12boctalzydro-Z,2-dimeth0xy-4,4-dimezhylind0l0[2,3-a]quinolizinehydr0chloride.A solution of 1.53 g. (5.70 mole) of the free basedescribed above was suspended in 50 ml. of cold methanol. Hydrogenchloride was slowly bubbled into the methanol at to The free basedissolved as the hydrochloride formed. An equal volume of ether wasadded and the solution was allowed to cool. The white precipitate whichformed was filtered, Washed with ether-methanol and dried to give 1.44g. (72%) of the ketal hydrochloride, M.P. 197-199 (dec.);

0 0, absorption absent J,2,3,4,6,7,12,12b Octahydro 2 0x0 4 Phenyl.indolo[2,3-a1Quinolizine, Hydrochloride and Dimethyl Ketal HydrochlorideA. N-tryptaminomethylene benzalacetone.-This compound was preparedaccording to the procedure given in Example l-B. The intermediate wasobtained as a dark yellow powder in quantitative yield. For analysis asample was recrystallized from benzene-Skelly B as a yellow powder, M.P.124-126";

11358 1640 (m.) and 1610 (s.) 00117 REES Analysis.Calcd. for C H N O: N,8.86. Found: N, 8.65.

B. 1-(2-0x0-4-phenyl-3-butenyl) -1,2,3,4-tetrahydr0-B- carbolznehydrochloride.-This compound was prepared in 57% yield according to theprocedure described in Example l-C. Recrystallization from aqueousmethanol produced the analytical sample, M.P. 218-2l9 (dec.);

1650, 1620 and 1600 cm." (M0504 11 1720 cm.- (Normal ketone C=O)Analysis-Calm. for C H N O: N (basic), 4.43. Found: N, 4.35 (titration).

A sample of the free base suspended in hot isopropyl alcohol was treatedwith hydrogen chloride. The mixture was warmed a few minutes on thesteam bath and filtered. The hydrochloride had M.P. 202-203 (dec.);

Analysis.-Calcd. for C H CIN O: Cl, 10.06.

Found: Cl, 9.92.

D. 1,2,3,4,6,7,12,12b octalzydro 2,2-dimeth0xy 4-phenylind0lo[2,3-a]quinolizine hydr0chl0ride.--The dimethyl ketalhydrochloride was obtained in 57% yield from methanol-ether, M.P. 173174(dec.);

#25; only Weak band present in 0:0 region Analysis.-Calcd. for C H ClN OCl, 8.90. Found: Cl, 8.81.

EXAMPLE III I,2,3,4,4a,6,7,12,12b,13,14,14a Dodecahydro 14 0x0-benz[f]Indolo[2,3-a]Quinolizine and Hydrochloride A. 1 (Nlryptaminomethylene)acetylcycl0hexene.- This compound was obtained as athick yellow sirup (quantitative yield) according to Example 1-B usingtryptamine hydrochloride and the sodiohydroxymethyh ene derivative ofl-acetylcyclohexene. A sample of this crude product was recrystallizedfrom benzene-Skelly B in the form of a yellow powder, M.P. 102-1035"; #35,9 1e20, 1540 and 1480 cmflgk 340 my, 6 21,700

max. 9 4Analysis.-Calcd. for C H N N, 9.52. Found: N,

B. 1 (l-acetylcyclohexenyl)1,2,3,4 -tetrahydr0-fi-carbolinehydr0chl0ride.The ivory-colored hydrochloride, M.P. 215-220 (dec.), wasobtained in 79% yield according to procedure 1-C. The infrared spectrum(KBr) showed a band at 1655 cm.- and shoulder at 1630 cm.- (conj.,ketone C=O).

Analysis.--Calcd. for C H ClN O: Cl, 10.73. Found: Cl, 10.71.

C. 1, 2, 3, 4, 4a, 6, 7, 12, 12b, 13, 14, 14a-dodecahydr0-l4-oxobenz[f]indolo[2,3 -a]quinolizine and hydrochloride.Thisindoloquinol-izine was obtained in 88% yield according to the methoddescribed in Example 1-D. The compound has M.P. 216217 and showed anormal ketone carbonyl band at 1710 cm? in the infrared. An analyticalsample was prepared by recrystallization from methanol, M.P. 219-220.

Analysis-Calcd. for C H N O: N (basic), 4.76. Found: N, 4.74(titration).

The hydrochloride was obtained from methanol in the form of small whitecrystals, M.P. sintering 200.

Analysis.Calcd. for C H ClN O: Cl, 10.73. Found: Cl, 10.70.

As pointed out above, the compounds thus produced may serve as usefulintermediates in the synthesis of yohimbine type alkaloids. For example,the reaction of V with 4-diethyIlaminoIbutan-2-one methoidide under theconditions of the Robinson reaction (E. C. du Feu, J. McQuillin and R.Robinson, J. Chem. Soc. 53 (1937) and G. B. Kline, I. Am. Chem. Soc. 81,225 1 (1959) should result in the formation of the pentacyclic structureVI which is a A-15,16-yohimben-17-one OK H is:

In summary this invention provides certain octahydro oxoindoloquinolizines and dodecahydro oxobenz-indolo quinolizines correspondingto the formulas given above. These compounds are useful as intermediatesin the synthesis of yohimbine type alkaloids.

What is claimed is:

1. 1, 2, 3, 4, 6, 7, 12, 12b-ootahydro-2-oxo-4,4-dimethylindolo[2,3-a]quinolizine dimethyl ketal.

2. 1, 2, 3, 4, 6, 7, 12, 12b-octahydro-2-oxo-4-phenylindolo [2,3-a]quinolizine.

3. 1, 2, 3, 4, 6, 7, 12, 12b-octahydro-Z-oXo-4-phenylindolo [2,3-a]quinol-izine dimethyl ketal.

4. 1, 2, 3, 4, 4a, 6, 7, 12, 12b, 13, 14, 14a-dodecahydro- 14-oxobenz[f] indolo[2,3-a] quinolizine.

5. A process for the preparation of a compound having the formulawhereinR and R each is selected from the group consisting of hydrogen and loweralkyl and R is a member selected from the group consisting of alkyl andaryl which comprises reacting tryptamine hydrochloride with a compoundhaving the formulain aqueous solution, reacting the product of thisreaction, having the formulawith methanolic hydrogen chloride to producea compound having the formulaand reacting this compound with sodiumbicarbonate and aqueous ethanol to form the product having the formula-N g R:

6. A process according to claim 7 wherein the product having theformulais reacted with methanolic hydrogen chloride to give acorresponding dimethyl ketal having the formula- H 00 OCHz 8 to produce1-(l-acetylcyclohexenyl)-1,2,3,4-tetrahydrofi-carboline having theformulaand reacting said product with sodium bicarbonate and Whlchcompnses reactmg 'tryptamme hydmchlonde Wlth aqueous ethanol to producethe desired product having the sodiohydroxymethylene derivative ofl-acetylcyclothe formula hexene in aqueous solution to producel-(N-tryptarnino- 5 methylene) acetylcyclohexene having the formula- 7.A process for the preparation of a compound having the formula- 1 (W INH t r I A 25 References Cited in the file of this patent UNITED STATESPATENTS reacting this product with methanolic hydrogen chloride2,908,686 Cohen et al Oct. 13, 1959

4. 1, 2, 3, 4, 4A, 6, 7, 12, 12B, 13, 14, 14A-DODECAHYDRO 14-OXOBENZF!INDOLO 2,3-A!QUINOLIZINE.
 5. A PROCESS FOR THE PREPARATION OF ACOMPOUND HAVING THE FORMULA-